Malignant gliomas represent 40 percent of primary brain tumors and patients with these tumors die within 1-2 years despite current conventional therapy (surgery, radiation, and chemotherapy). Hypoxia, a physiological difference between normal and tumor tissue, is a major factor in the resistance of cancer cells to radio- and chemo-therapies. We propose to exploit this difference to construct a novel type of cancer therapy adenovirus that will target hypoxic tumor cells and, therefore complement radio- and chemotherapies. We will generate an adenovirus that selectively replicates within hypoxic tumor cells. This will lead to oncolysis of these cells because adenoviruses have a cytolytic cycle. To achieve hypoxia-specific replication, we will place the adenoviral E1A gene under the control of an exogenous hypoxia-regulated promoter (HYPR-Ad). The E1A gene encodes an early viral protein essential for the initiation of adenovirus replication. Moreover, we will augment the anti-tumor capability of this oncolytic virus by having it function as a therapeutic gene delivery vehicle. We will introduce into the HYPR viral vector an expression cassette for the angiogenesis inhibitor angiostatin (HYPRA-Ad). The production of this angiogenesis inhibitor by infected hypoxic cells will generate a field effect that should counteract the action of the angiogenic stimulators released by these cells in response to hypoxia. In addition, it should reduce the expansion of noninfected and normoxic tumor cells by preventing them from recruiting new vascular supply. These recombinant adenoviruses will be studied for their ability to infect, replicate, and induce cytolysis of cells derived from glioma under normoxic and hypoxic conditions in vitro. Subsequently, the therapeutic efficacy of these viruses will be examined using subcutaneous and intracerebral human glioma models in mice and the efficacy of their combination with standard radio- and chemo-therapy will be evaluated. This tumor therapy approach is novel in that these viruses can provide direct oncolytic therapy as well as deliver adjuvant gene therapy. Most importantly, these viruses have broad applicability to treat ALL cancer types that develop hypoxia regardless of their tissue of origin and genetic composition. The translation of these preclinical studies have the potential to directly benefit human health by improving the survival of cancer patients.